Novel x-ray contrast agents, compositions and methods

ABSTRACT

The compound N-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N&#39;-methyl-2,4,6-triiodoisophthalamide and similar such compounds may be used as x-ray contrast agents which are water-soluble, safe and in an aqueous solution are non-viscous. Methods of preparing N-(2,3-dihydroxypropyl)-5-[N-(2-hdyroxyethyl)glycolamido]-N&#39;-methyl-2,4,6-triiodoisophthalamide are provided.

BACKGROUND OF THE INVENTION

This invention relates to x-ray contrast agents and, more particularly,to novel nonionic x-ray contrast agents, radiological compositionscontaining such agents and methods for X-ray visualization utilizingsuch compositions.

Nonionic contrast agents for intravascular and central nervous systemvisualization are complex molecules. As is known, the iodine in themolecule provides opacification to the x-rays. The remainder of themolecule provides the framework for transport of the iodine atoms.However, the structural arrangement of the molecule is important inproviding stability, solubility and biological safety in various organs.A stable carbon-iodine bond is achieved in most compounds by attachingit to an aromatic nucleus. An enhanced degree of solubility as well assafety is conferred on the molecule by the addition of suitablesolubilizing and detoxifying groups.

Futhermore, several features are desirable for intravascular and centralnervous system nonionic agents. These include (1) maximum opacity tox-rays, (2) biological safety, (3) high water solubility, (4) chemicalstability, (5) low osmolality, (6) no ionic charge, and (7) lowviscosity.

There is a continuing need for nonionic contrast agents which meet allor substantially all the foregoing criteria. In addition to preparingthe stable, watersoluble and safe agents, the recent studies have beenin the development of low osmolality agents. Studies have shown thathigh osmolality can be correlated with many of the undesirablephysiologic adverse reactions after the x-ray contrast mediumintravenous injection, e.g. neausea, vomiting, heat and pain. The mostrecent major improvement is the introduction of low osmolar, nonionicagents, such as iopamidol, iohexol and ioversol. These new low osmolaragents provide patient comfort by causing less nausea and vomiting onintravenous injection and much less pain on peripheral arterialinjection.

SUMMARY OF THE INVENTION

Among the several objects of the invention may be noted the provision ofnovel nonionic contrast agents, radiological compositions and methodsfor x-ray visualization; and the provision of such agents which aresubstantially non-toxic and meet the other criteria desired for nonioniccontrast agents. Other objects and features will be in part apparent andin part pointed out hereinafter.

Briefly, the present invention is directed to compounds of the formula:##STR1## wherein the X groups may be the same or different selected froma group consisting of hydroxy and alkoxy, wherein the alkoxy groupcontains from 1 to 6 carbon atoms, such as for example methoxy, toreduce lipophilicity.

The invention is specifically directed to the compoundN-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide.The invention is also directed to radiological compositions containingsuch a compound and methods for utilizing such a compound in x-rayvisualization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, it has now been found thatcompounds of the formula set out above are suitable for use as nonionicx-ray contrast agents. More specifically in the practice of theinvention, the compoundN-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-N'-methyl-2,4,6-triiodoisophthalamidemay be used as a nonionic x-ray contrast agent. This compound iswater-soluble, safe (i.v. LD₅₀ in mice is 16.1 gI/Kg) and its aqueoussolution is non-viscous (6.3 cps at 25° as a 32% I solution).Particularly, it exhibits remarkably low osmolality (400 mOsm/Kg as a32% I solution). This agent may be used in various radiographicprocedures including those involving cardiography, coronaryarteriography, aortography, cerebral and peripheral angiography,orthography, intravenous pyelography and urography.

In further accordance with the present invention, radiologicalcompositions may be prepared containing the aforementioned compound asan x-ray contrast agent together with a pharmaceutically acceptableradiological vehicle.

Pharmaceutically acceptable radiological vehicle's include those thatare suitable for injection such as aqueous buffer solutions; e.g.,tris(hydroxymethyl) amino methane (and its salts), phosphate, citrate,bicarbonate, etc., sterile water for injection, physiological saline,and balanced ionic solutions containing chloride and/or bicarbonatesalts of normal blood plasma cations such as Ca, Na, K and Mg. Otherbuffer solutions are described in Remington's Practice of Pharmacy,Eleventh Edition, for example on page 170. The vehicles may contain achelating amount, e.g., a small amount, of ethylenediamine tetraaceticacid, the calcium disodium salt, or other pharmaceutically acceptablechelating agent

The concentration of the x-ray contrast agent of the present inventionin the pharmaceutically acceptable vehicle, for example an aqueousmedium, varies with the particular field of use. A sufficient amount ispresent to provide satisfactory x-ray visualization. For example, whenusing aqueous solutions for angiography, the concentration of iodine isgenerally 140-400 mg/ml and the dose is 25-300 ml.

The radiological composition is administered so that the contrast agentremains in the living animal body for about 2 to 3 hours, although bothshorter and longer residence periods are normally acceptable. Thus,N-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamidemay be formulated for vascular visualization conveniently in vials orampoules containing 10 to 500 ml. of an aqueous solution.

The radiological compositions of the invention may be used in the usualway in x-ray procedures. For example, in the case of selective coronaryarteriography, a sufficient amount of the radiological composition toprovide adequate visualization is injected into the coronary system andthen the system is scanned with a suitable device such as a fluoroscope.

The compoundN-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamideand the intermediates therefor may be prepared in accordance with theprocedures set out below. All temperature designations are in degreescentigrade.

The following examples illustrate the practice of the invention.

EXAMPLE IN-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide

A. Preparation of 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoylchloride (2) ##STR2##

The flask was charged with thionyl chloride (600 ml, 978.6 g, 8.23 mol)and 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoic acid (320 g, 0.56mol) was added in portions with stirring. The mixture was refluxed forone hour and an additional 100 ml of thionyl chloride was added.Refluxing was continued for 1.5 hours (total reflux time: 2.5 hours)until TLC indicated that the reaction was complete. Thionyl chloride wasremoved by vacuum distillation (30° C., 75 mmHg) until the consistencyof the residue was pasty. The remaining traces of thionyl chloride wereremoved by three consecutive vacuum codistillations with 200 ml of THF.The resulting yellow paste was dissolved in 600 ml of THF and immersedin an ice bath while 500 ml of saturated NaCl was added. The pH of theaqueous layer (<1) was adjusted to approximately 6.9 with solid sodiumcarbonate (173 g, 1.63 mol) The mixture was filtered and the filter cakewas washed with 200 ml of THF. The wash was combined with the motherliquor which was then allowed to separate into two layers. The organiclayer was washed with 200 ml of saturated NaCl, the aqueous layer with150 ml THF: the organic layers were combined and dried over 180 g ofcalcium chloride beads for one hour. The solution was concentrated to avolume of 400 ml and stirred with 200 ml of dry toluene for 16 hours.The creamy white solid thus formed was filtered, washed with 2×100 ml ofdry cold toluene and dried under vacuum to give 228 g of product 2 (0.39mol, 69%) as a pale yellow solid. ¹³ C NMR (75.5 MHz, DMSO, ref. DMSO at39.5 ppm): 170.2, 150.4, 148.9, 148.7, 83.0, 75.3, 70.1, 25.8. TLC: Onespot (EtOAc/MeOH/HOAc, 10/5/1).

B. Preparation of5-Acetoxyacetamido-3-methylcarbamoyl2,4,6-triiodobenzoyl chloride (3)##STR3##

To a slurry of (2) (170 g, 0.29 mol) in 350 ml of N,N-dimethylacetamide(DMAc) was added 4-dimethylaminopyridine (DMAP) (1.86 g, 0.015 mol). Themixture was cooled to 0° C. and acetoxyacetyl chloride (62 ml, 78.6 g,0.58 mol) was added dropwise, keeping the temperature <5° C. The mixturewas stirred at 30° C. for 16 hours. The reaction mixture containing thesolid white product was immersed in an ice bath for 2 hours, filtered,stirred with cold THF (1100 ml) for 1 hour, filtered and dried undervacuum for 2 days to give 190 g of product 3 (0.30 mol, 95%) as a whitesolid. ¹³ C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 170.6, 170.2,169.9, 166.1, 166.0, 151.7, 149.8, 143.6, 143.5, 103.4, 97.0, 88.8,62.4, 26.0, 20.6.

C. Preparation ofN(2,3-dihydroxypropyl)-5-acetoxyacetamido-N'-methyl-2,4,6-triiodoisophthalamide##STR4##

A solution of 3-amino-1,2-propanediol (APD) (36 g, 0.40 mol) in 100 mldry DMAc was added dropwise to a slurry of (3) (200 g, 0.29 mol) andsodium carbonate (42 g, 0.40 mol) in 450 ml of dry DMAc, keeping thetemperature at 25° C. with the application of an ice bath. Following theaddition, the mixture was stirred at 35° C. for 22 hours.

Because a trace of starting material was still present, 4.2 g (0.04 mol)of Na₂ CO₃ and 3.6 g (0.04 mol) of APD in 40 ml of DMAc were added. Thismixture was stirred at 35° C. for 3.5 hours, at which time the reactionwas complete. Approximately 450 g of DMAc was removed by rotaryevaporation; the remaining oil was added dropwise to 1000 ml of acetoneimmersed in an ice bath, with stirring. After standing for 4.5 hours,the resultant solid was filtered, washed with 3×200ml of hexane, anddried under vacuum for 2.5 days to give 153 g of product 4 (0.21 mol,71%) as an off-white powder (one spot by TLC, CHCl₃ /MeOH:75/25).

D. Preparation ofN-(2,3-dihydroxypropyl)-5-glycolamido-N'-methyl-2,4,6-triiodoisophthalamide(5) ##STR5##

To a slurry of (4) (100 g, 0.13 mol) in 800 ml of MeOH was added 200 mlof 1.0N NaOH (8.0 g, 0.2 mol) as a steady stream over a 5 minute period.The solution was allowed to stir 16 hours. The pH (10.8) was adjusted to7.0 with conc. HCl, and the solvents were removed by rotary evaporationto leave a cream colored paste. After stirring with 200 ml of cold waterfor 10 minutes, the solid product was filtered, washed with 2×300 ml ofcold water, and dried in a vacuum desiccator for 24 hours to give 59 gof product 5 (0.08 mol, 63%) as a white solid.

¹³ C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 170.9, 170.4, 170.1,150.7, 150.4, 143.3, 99.3, 90.3, 90.28, 70.1, 64.0, 61.9, 42.6, 25.9.One spot by TLC (CHCl₃ /MeOH, 75/25).

E. Preparation ofN-(2,3-diacetoxypropyl)-5-acetoxyacetamido-N'-methyl-2,4,6-triiodoisophthalamide(6) ##STR6##

4-Dimethylaminopyridine (0.42 g, 0.0035 mol) was added to a slurry of(5) (52 g, 0.074 mol) in 140 ml of dry DMAc. An ice bath was applied,and acetic anhydride (35 ml, 37 g, 0.37 mol) was added at such a rate asto maintain the temperature below 10° C. The ice bath was removed, andthe mixture was stirred at 45° C. for 4.5 hours, at which time anadditional 14 ml (14.8 g, 0.15 mol) of acetic anhydride was added, andthe solution was stirred at 45° C. for 16 hours. The resultant paleyellow solution which tested pure by TLC was stripped to an off-whitefoam (68 g), which was used as is in the following reaction. ¹³ C NMR(75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 171.5, 170.6, 170.4, 170.0,169.9, 168.4, 151.9, 151.2, 143.0, 100.2, 99.9, 69.7, 69.6, 64.5, 63.0,25.8, 21.3, 21.0, 20.5, 20.2. One spot by TLC (CHCl₃ /MeOH, 90/10).

F. Preparation ofN-(2,3-diacetoxypropyl)-5-[N-(2-acetoxyethylethyl)acetoxyacetamide]-N'-methyl-2,4,6-triiodoisophthalamide(7) ##STR7##

A slurry was formed by adding K₂ CO₃ (18.35 g, 0.133 mol) to a solutionof (6) (47.4 g, 0.057 mol) in 40 ml of DMSO. Bromoethylacetate (11.0 ml,16.58 g, 0.099 mol) was added in one portion and the reaction mixturewas stirred at 40° C. for 16 hours. At this point, 5.64 g (0.04 mol) K₂CO₃ and 5.64 ml (0.03 mol) bromoethylacetate were added and the mixturewas stirred at 40° C. for 7 more hours, then at room temperature (.sup.˜22° C.) four days. The additions were repeated (identical quantities),the mixture was stirred at 40° C. for 7 hours, and then at roomtemperature for 16 hours. The brown gum (58 g) of crude product (7)obtained after filtration followed by concentration was carried on tothe next step without purification.

G. Preparation ofN-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide(8) (MP-871) ##STR8##

To a solution of the gum (containing (7)) above in 225 ml of MeOH wasadded dropwise a methanolic solution of sodium methoxide (prepared from2.7 g, 0.068 mol of sodium metal and 225 ml MeOH) over a 30 minuteperiod, keeping the temperature below 0° C. with an isopropanol-dry icebath. The reaction was stirred at -5° to 0° C. for 2.5 hours, the pH wasadjusted to 4.0 with conc. HOAc, and the solution was concentrated to agum (52.4 g). Two consecutive preparative HPLC treatments yielded 19 gof a white glassy solid, 98.1% pure by HPLC. The solid was dissolved inapproximately 400 ml of water and stirred with 0.38 g of activatedcharcoal at 60° C. for 2 hours, then at room temperature for 16 hours.The solution was filtered and passed through a column of amberliteIR-458 and IR-120 ion exchange resins (10 ml of each, Rohm and HaasCompany). The water was evaporated to give 15 g of product 8 (0.02 mol)as a white glassy solid.

HPLC: 99.9 area %, one peak with a tailing shoulder, 31.5 minutes: 1.7ml/min: H₂ O/MeOH:98/2; ODS packing.

¹³ C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 171.8, 71.6, 170.4,170.1, 170.0, 151.9, 152.0, 151.9, 151.7, 145.6, 100.7, 100.5, 100.2,92.4, 70.4, 70.3, 70.0, 64.1, 64.0, 61.8, 58.6, 58.5, 51.4, 51.3, 42.5,42.4, 26.0, 25.9.

What is claimed is:
 1. A radiological composition containing a compoundof the formula: ##STR9## wherein the X groups may be the same ordifferent selected from a group consisting of hydroxy and alkoxycontaining from one to six carbon atoms, in an effective amount toprovide satisfactory x-ray visualization together with apharmaceutically acceptable radiological vehicle.
 2. A radiologicalcomposition as set forth in claim 1 wherein said compound isN-(2,3-Dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide.3. In a method for x-ray visualization wherein a radiologicalcomposition containing an x-ray contrast agent in a pharmaceuticallyacceptable radiological vehicle is administered in an effective amountto provide adequate visualization and thereafter x-ray visualization iscarried out using as the radiological composition, a compositioncontaining a compound of the formula: ##STR10## wherein the X groups maybe the same or different selected from a group consisting of hydroxy andalkoxy containing from one to six carbon atoms.
 4. A method as set forthto claim 3 wherein said compound isN-(2,3-Dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide.5. A compound of the formula: ##STR11## wherein the X groups may be thesame or different selected from a group consisting of hydroxy and alkoxycontaining from one to six carbon atoms.
 6. A compound of claim 5 whichisN-(2,3-Dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-N'-methyl-2,4,6-triiodoisophthalamide.